tbuckley/cabot-search huggingface dataset:
Aberrant chromatin reorganization in cells from diseased fibrous connective tissue in response to altered chemomechanical cues
Authors: Su-Jin Heo, Shreyasi Thakur, Xingyu Chen, Claudia Loebel, Boao Xia, Rowena McBeath, Jason A. Burdick, Vivek B. Shenoy, Robert L. Mauck, Melike Lakadamyali
Journal: Nature Biomedical Engineering (2022)
Long non-coding RNA SNHG6 couples cholesterol sensing with mTORC1 activation in hepatocellular carcinoma
Authors: Fangzhou Liu, Tian Tian, Zhen Zhang, Shanshan Xie, Jiecheng Yang, Linyu Zhu, Wen Wang, Chengyu Shi, Lingjie Sang, Kaiqiang Guo, Zuozhen Yang, Lei Qu, Xiangrui Liu, Jian Liu, Qingfeng Yan, Huai-qiang Ju, Wenqi Wang, Hai-long Piao, Jianzhong Shao, Tianhua Zhou, Aifu Lin
Journal: Nature Metabolism (2022)
Gene–environment correlations across geographic regions affect genome-wide association studies
Authors: Abdel Abdellaoui, Conor V. Dolan, Karin J. H. Verweij, Michel G. Nivard
Journal: Nature Genetics (2022)

Abstract Gene–environment correlations affect associations between genetic variants and complex traits in genome-wide association studies (GWASs). Here we showed in up to 43,516 British siblings that educational attainment polygenic scores capture gene–environment correlations, and that migration extends these gene–environment correlations beyond the family to broader geographic regions. We then ran GWASs on 56 complex traits in up to 254,387 British individuals. Controlling for geographic regions significantly decreased the heritability for socioeconomic status (SES)-related traits, most strongly for educational attainment and income. For most traits, controlling for regions significantly reduced genetic correlations with educational attainment and income, most significantly for body mass index/body fat, sedentary behavior and substance use, consistent with gene–environment correlations related to regional socio-economic differences. The effects of controlling for birthplace and current address suggest both passive and active sources of gene–environment correlations. Our results show that the geographic clustering of DNA and SES introduces gene–environment correlations that affect GWAS results.
Atezolizumab versus chemotherapy in advanced or metastatic NSCLC with high blood-based tumor mutational burden: primary analysis of BFAST cohort C randomized phase 3 trial
Authors: Solange Peters, Rafal Dziadziuszko, Alessandro Morabito, Enriqueta Felip, Shirish M. Gadgeel, Parneet Cheema, Manuel Cobo, Zoran Andric, Carlos H. Barrios, Masafumi Yamaguchi, Eric Dansin, Pongwut Danchaivijitr, Melissa Johnson, Silvia Novello, Michael S. Mathisen, Sarah M. Shagan, Erica Schleifman, Jin Wang, Mark Yan, Simonetta Mocci, David Voong, David A. Fabrizio, David S. Shames, Todd Riehl, David R. Gandara, Tony Mok
Journal: Nature Medicine (2022)

Tumor mutational burden (TMB) is being explored as a predictive biomarker for cancer immunotherapy outcomes in non-small cell lung cancer. BFAST (NCT03178552)-an open-label, global, multicohort trial-evaluated the safety and efficacy of first-line targeted therapies or immunotherapy in patients with unresectable Stage IIIB or IV advanced or metastatic non-small cell lung cancer who were selected for biomarker status using blood-based targeted next-generation sequencing. In the Phase 3 cohort C evaluating blood-based (b)TMB as a biomarker of atezolizumab efficacy, patients with bTMB of ≥10 (N = 471) were randomized 1:1 to receive atezolizumab or platinum-based chemotherapy per local standard of care. Cohort C did not meet its primary endpoint of investigator-assessed progression-free survival in the population with bTMB of ≥16 (hazard ratio, 0.77; 95% confidence interval: 0.59, 1.00; P = 0.053). Adverse events leading to treatment withdrawal occurred in 10% of patients in the atezolizumab arm and 20% in the chemotherapy arm. Adverse events of special interest occurred in 42% of patients in the atezolizumab arm and 26% in the chemotherapy arm. A prespecified exploratory analysis compared the bTMB clinical trial assay with the FoundationOne Liquid Companion Diagnostic assay and showed high concordance between assays. Additional exploration of bTMB to identify optimal cutoffs, confounding factors, assay improvements or cooperative biomarkers is warranted.
Evolutionary Tuning of Transient Receptor Potential Ankyrin 1 Underlies the Variation in Heat Avoidance Behaviors among Frog Species Inhabiting Diverse Thermal Niches
Authors: Shigeru Saito, Claire T Saito, Takeshi Igawa, Nodoka Takeda, Shohei Komaki, Toshio Ohta, Makoto Tominaga
Journal: Molecular Biology and Evolution (2022)

Abstract Environmental temperature is a critical factor for all forms of life, and thermal tolerance defines the habitats utilized by a species. Moreover, the evolutionary tuning of thermal perception can also play a key role in habitat selection. Yet, the relative importance of thermal tolerance and perception in environmental adaptation remains poorly understood. Thermal conditions experienced by anuran tadpoles differ among species due to the variation in breeding seasons and water environments selected by parental frogs. In the present study, heat tolerance and avoidance temperatures were compared in tadpoles from five anuran species that spatially and temporally inhabit different thermal niches. These two parameters were positively correlated with each other and were consistent with the thermal conditions of habitats. The species difference in avoidance temperature was 2.6 times larger than that in heat tolerance, suggesting the importance of heat avoidance responses in habitat selection. In addition, the avoidance temperature increased after warm acclimation, especially in the species frequently exposed to heat in their habitats. Characterization of the heat-sensing transient receptor potential ankyrin 1 (TRPA1) ion channel revealed an amphibian-specific alternatively spliced variant containing a single valine insertion relative to the canonical alternative spliced variant of TRPA1, and this novel variant altered the response to thermal stimuli. The two alternatively spliced variants of TRPA1 exhibited different thermal responses in a species-specific manner, which are likely to be associated with a difference in avoidance temperatures among species. Together, our findings suggest that the functional change in TRPA1 plays a crucial role in thermal adaptation processes.
BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH
Authors: Ritesh K. Baboota, Aidin Rawshani, Laurianne Bonnet, Xiangyu Li, Hong Yang, Adil Mardinoglu, Tamar Tchkonia, James L. Kirkland, Anne Hoffmann, Arne Dietrich, Jeremie Boucher, Matthias Blüher, Ulf Smith
Journal: Nature Metabolism (2022)

Abstract The role of hepatic cell senescence in human non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is not well understood. To examine this, we performed liver biopsies and extensive characterization of 58 individuals with or without NAFLD/NASH. Here, we show that hepatic cell senescence is strongly related to NAFLD/NASH severity, and machine learning analysis identified senescence markers, the BMP4 inhibitor Gremlin 1 in liver and visceral fat, and the amount of visceral adipose tissue as strong predictors. Studies in liver cell spheroids made from human stellate and hepatocyte cells show BMP4 to be anti-senescent, anti-steatotic, anti-inflammatory and anti-fibrotic, whereas Gremlin 1, which is particularly highly expressed in visceral fat in humans, is pro-senescent and antagonistic to BMP4. Both senescence and anti-senescence factors target the YAP/TAZ pathway, making this a likely regulator of senescence and its effects. We conclude that senescence is an important driver of human NAFLD/NASH and that BMP4 and Gremlin 1 are novel therapeutic targets.
Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition
Authors: Peter B. Gilbert, Yunda Huang, Allan C. deCamp, Shelly Karuna, Yuanyuan Zhang, Craig A. Magaret, Elena E. Giorgi, Bette Korber, Paul T. Edlefsen, Raabya Rossenkhan, Michal Juraska, Erika Rudnicki, Nidhi Kochar, Ying Huang, Lindsay N. Carpp, Dan H. Barouch, Nonhlanhla N. Mkhize, Tandile Hermanus, Prudence Kgagudi, Valerie Bekker, Haajira Kaldine, Rutendo E. Mapengo, Amanda Eaton, Elize Domin, Carley West, Wenhong Feng, Haili Tang, Kelly E. Seaton, Jack Heptinstall, Caroline Brackett, Kelvin Chiong, Georgia D. Tomaras, Philip Andrew, Bryan T. Mayer, Daniel B. Reeves, Magdalena E. Sobieszczyk, Nigel Garrett, Jorge Sanchez, Cynthia Gay, Joseph Makhema, Carolyn Williamson, James I. Mullins, John Hural, Myron S. Cohen, Lawrence Corey, David C. Montefiori, Lynn Morris
Journal: Nature Medicine (2022)

Abstract The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01. Using AMP trial data, here we show that the predicted serum neutralization 80% inhibitory dilution titer (PT 80 ) biomarker—which quantifies the neutralization potency of antibodies in an individual’s serum against an HIV-1 isolate—can be used to predict HIV-1 prevention efficacy. Similar to the results of nonhuman primate studies, an average PT 80 of 200 (meaning a bnAb concentration 200-fold higher than that required to reduce infection by 80% in vitro) against a population of probable exposing viruses was estimated to be required for 90% prevention efficacy against acquisition of these viruses. Based on this result, we suggest that the goal of sustained PT 80 &gt;200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. We propose the PT 80 biomarker as a surrogate endpoint for evaluation of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines.
Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis
Authors: Yuye Yin, Xinyi Yang, Shusheng Wu, Xinyu Ding, Huamin Zhu, Xuehui Long, Yuliang Wang, Sulan Zhai, Yun Chen, Nan Che, Jingjing Chen, Xiaoming Wang
Journal: Nature Immunology (2022)
Historical Contingency Drives Compensatory Evolution and Rare Reversal of Phage Resistance
Authors: Reena Debray, Nina De Luna, Britt Koskella
Journal: Molecular Biology and Evolution (2022)

Abstract Bacteria and lytic viruses (phages) engage in highly dynamic coevolutionary interactions over time, yet we have little idea of how transient selection by phages might shape the future evolutionary trajectories of their host populations. To explore this question, we generated genetically diverse phage-resistant mutants of the bacterium Pseudomonas syringae. We subjected the panel of mutants to prolonged experimental evolution in the absence of phages. Some populations re-evolved phage sensitivity, whereas others acquired compensatory mutations that reduced the costs of resistance without altering resistance levels. To ask whether these outcomes were driven by the initial genetic mechanisms of resistance, we next evolved independent replicates of each individual mutant in the absence of phages. We found a strong signature of historical contingency: some mutations were highly reversible across replicate populations, whereas others were highly entrenched. Through whole-genome sequencing of bacteria over time, we also found that populations with the same resistance gene acquired more parallel sets of mutations than populations with different resistance genes, suggesting that compensatory adaptation is also contingent on how resistance initially evolved. Our study identifies an evolutionary ratchet in bacteria–phage coevolution and may explain previous observations that resistance persists over time in some bacterial populations but is lost in others. We add to a growing body of work describing the key role of phages in the ecological and evolutionary dynamics of their host communities. Beyond this specific trait, our study provides a new insight into the genetic architecture of historical contingency, a crucial component of interpreting and predicting evolution.
Preventing pressure injuries among patients in the intensive care unit: insights gained
Authors: Fiona Coyer, Sonia Labeau, Stijn Blot
Journal: Intensive Care Medicine (2022)

Why, in the first quarter of the twenty-first century, do pressure injuries (PIs) remain a perennial problem for patients admitted in the intensive care unit (ICU)?PIs are associated with substantial morbidity, thereby burdening the patient and the healthcare system through pain, emotional distress, recovery, and prolonged hospitalization [1].ICU patients have one of the highest incidence and prevalence rates of PI as they often combine a high index of acute illness with underlying conditions (e.g., chronic obstructive pulmonary disease) facilitating skin breakdown [2,3].ICU patients have a nearly fourfold higher risk for hospital-acquired PI compared to non-ICU patients [4].International data from 1117 ICUs in 90 countries highlighted an ICU-acquired PI prevalence of 16.2% (95% confidence interval [CI], 15.6-16.8)[5].Compared with countries with a high-income economy, the prevalence of ICU-acquired PIs appears higher in low-and lower-middle-income economies (odds ratio 1.8, 95% CI 1-3.3) [5].Nearly one-third of all PI occur on the sacrum and heels [2,5].Device-related PIs accounts for up to 74% of all reported ICU-acquired PIs [6].Albeit that generic PI risk scores have demonstrated their value in non-ICU populations, prediction of ICU-acquired PIs remains challenging because of variations in heterogeneity, and the determinative importance of local case-mix, and organizational factors [7,8].Anyhow, ICU-specific risk factors often include aspects of organ support such as vasopressor use, mechanical ventilation, and renal replacement therapy [5].Therefore, ICU patients represent a unique population where the risk for PIs is arguably different in many ways from other patient groups.
Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer
Authors: Daniel Cui Zhou, Reyka G. Jayasinghe, Siqi Chen, John M. Herndon, Michael D. Iglesia, Pooja Navale, Michael C. Wendl, Wagma Caravan, Kazuhito Sato, Erik Storrs, Chia-Kuei Mo, Jingxian Liu, Austin N. Southard-Smith, Yige Wu, Nataly Naser Al Deen, John M. Baer, Robert S. Fulton, Matthew A. Wyczalkowski, Ruiyang Liu, Catrina C. Fronick, Lucinda A. Fulton, Andrew Shinkle, Lisa Thammavong, Houxiang Zhu, Hua Sun, Liang-Bo Wang, Yize Li, Chong Zuo, Joshua F. McMichael, Sherri R. Davies, Elizabeth L. Appelbaum, Keenan J. Robbins, Sara E. Chasnoff, Xiaolu Yang, Ashley N. Reeb, Clara Oh, Mamatha Serasanambati, Preet Lal, Rajees Varghese, Jay R. Mashl, Jennifer Ponce, Nadezhda V. Terekhanova, Lijun Yao, Fang Wang, Lijun Chen, Michael Schnaubelt, Rita Jui-Hsien Lu, Julie K. Schwarz, Sidharth V. Puram, Albert H. Kim, Sheng-Kwei Song, Kooresh I. Shoghi, Ken S. Lau, Tao Ju, Ken Chen, Deyali Chatterjee, William G. Hawkins, Hui Zhang, Samuel Achilefu, Milan G. Chheda, Stephen T. Oh, William E. Gillanders, Feng Chen, David G. DeNardo, Ryan C. Fields, Li Ding
Journal: Nature Genetics (2022)

Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease.
Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities
Authors: Roberta Esposito, Taisia Polidori, Dominik F. Meise, Carlos Pulido-Quetglas, Panagiotis Chouvardas, Stefan Forster, Paulina Schaerer, Andrea Kobel, Juliette Schlatter, Erik Kerkhof, Michaela Roemmele, Emily S. Rice, Lina Zhu, Andrés Lanzós, Hugo A. Guillen-Ramirez, Giulia Basile, Irene Carrozzo, Adrienne Vancura, Sebastian Ullrich, Alvaro Andrades, Dylan Harvey, Pedro P. Medina, Patrick C. Ma, Simon Haefliger, Xin Wang, Ivan Martinez, Adrian F. Ochsenbein, Carsten Riether, Rory Johnson
Journal: Cell Genomics (2022)

Long noncoding RNAs (lncRNAs) are widely dysregulated in cancer, yet their functional roles in cancer hallmarks remain unclear. We employ pooled CRISPR deletion to perturb 831 lncRNAs detected in KRAS-mutant non-small cell lung cancer (NSCLC) and measure their contribution to proliferation, chemoresistance, and migration across two cell backgrounds. Integrative analysis of these data outperforms conventional "dropout" screens in identifying cancer genes while prioritizing disease-relevant lncRNAs with pleiotropic and background-independent roles. Altogether, 80 high-confidence oncogenic lncRNAs are active in NSCLC, which tend to be amplified and overexpressed in tumors. A follow-up antisense oligonucleotide (ASO) screen shortlisted two candidates,
A regulatory network of Sox and Six transcription factors initiate a cell fate transformation during hearing regeneration in adult zebrafish
Authors: Erin Jimenez, Claire C. Slevin, Wei Song, Zelin Chen, Stephen C. Frederickson, Derek Gildea, Weiwei Wu, Abdel G. Elkahloun, Ivan Ovcharenko, Shawn M. Burgess
Journal: Cell Genomics (2022)

Using adult zebrafish inner ears as a model for sensorineural regeneration, we ablated the mechanosensory receptors and characterized the single-cell epigenome and transcriptome at consecutive time points during hair cell regeneration. We utilized deep learning on the regeneration-induced open chromatin sequences and identified cell-specific transcription factor (TF) motif patterns. Enhancer activity correlated with gene expression and identified potential gene regulatory networks. A pattern of overlapping Sox- and Six-family TF gene expression and binding motifs was detected, suggesting a combinatorial program of TFs driving regeneration and cell identity. Pseudotime analysis of single-cell transcriptomic data suggested that support cells within the sensory epithelium changed cell identity to a "progenitor" cell population that could differentiate into hair cells. We identified a 2.6 kb DNA enhancer upstream of the sox2 promoter that, when deleted, showed a dominant phenotype that resulted in a hair-cell-regeneration-specific deficit in both the lateral line and adult inner ear.
Molecular networks in atopic mothers impact the risk of infant atopy
Authors: Michaela Schedel, Sonia M. Leach, Matthew J. Strand, Thomas Danhorn, Morgan MacBeth, Anna V. Faino, Anne M. Lynch, Virginia D. Winn, Lindsay L. Munoz, Shannon M. Forsberg, David A. Schwartz, Erwin W. Gelfand, Pia J. Hauk
Journal: Allergy (2022)

The prevalence of atopic diseases has increased with atopic dermatitis (AD) as the earliest manifestation. We assessed if molecular risk factors in atopic mothers influence their infants' susceptibility to an atopic disease.Pregnant women and their infants with (n = 174, high-risk) or without (n = 126, low-risk) parental atopy were enrolled in a prospective birth cohort. Global differentially methylated regions (DMRs) were determined in atopic (n = 92) and non-atopic (n = 82) mothers. Principal component analysis was used to predict atopy risk in children dependent on maternal atopy. Genome-wide transcriptomic analyses were performed in paired atopic (n = 20) and non-atopic (n = 15) mothers and cord blood. Integrative genomic analyses were conducted to define methylation-gene expression relationships.Atopic dermatitis was more prevalent in high-risk compared to low-risk children by age 2. Differential methylation analyses identified 165 DMRs distinguishing atopic from non-atopic mothers. Inclusion of DMRs in addition to maternal atopy significantly increased the odds ratio to develop AD in children from 2.56 to 4.26. In atopic compared to non-atopic mothers, 139 differentially expressed genes (DEGs) were identified significantly enriched of genes within the interferon signaling pathway. Expression quantitative trait methylation analyses dependent on maternal atopy identified 29 DEGs controlled by 136 trans-acting methylation marks, some located near transcription factors. Differential expression for the same nine genes, including MX1 and IFI6 within the interferon pathway, was identified in atopic and non-atopic mothers and high-risk and low-risk children.These data suggest that in utero epigenetic and transcriptomic mechanisms predominantly involving the interferon pathway may impact and predict the development of infant atopy.
Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors
Authors: Amanda M. Nash, Samira Aghlara-Fotovat, Bertha Castillio, Andrea Hernandez, Aarthi Pugazenthi, Hyun-Sung Lee, Hee-Jin Jang, Annie Nguyen, Alexander Lu, Bryan M. Burt, Ravi K. Ghanta, Omid Veiseh
Journal: Clinical Cancer Research (2022)

Abstract Purpose: IL2 immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure. Experimental Design: We evaluated the therapeutic efficacy of IL2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis. Results: IL2 cytokine factories enabled 150× higher IL2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after 1 week of monotherapy treatment, and 7 of 7 of animals exhibited tumor eradication without recurrence when IL2 cytokine factories were combined with anti–programmed cell death protein 1 (aPD1). Furthermore, CyTOF analysis showed an increase in CD69+CD44+ and CD69−CD44+CD62L− T cells, reduction of CD86−PD-L1− M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages and MHC-II+ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use. Conclusions: IL2 cytokine factories led to the eradication of aggressive mouse malignant mesothelioma tumors and protection from tumor recurrence, and increased the therapeutic efficacy of aPD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL2-based delivery system. See related commentary by Palanki et al., p. 5010